Platelet-derived growth factor (PDGF) is a disulfide-linked dimer consisting of two related polypeptide chains, designated PDGF A and PDGF B, that are the products of distinct genes. The gene encoding the human PDGF B chain is the normal counterpart of the v-sis oncogene. Since PDGF A and PDGF B have distinct transforming phenotypes and cellular locations. we constructed twelve chimeric PDGF molecules to investigate structural regions of PDGF A or PDGF 8 associated with PDGF functions. The mechanistic basis of potent PDGF B transformation segregated with the activation of both alpha and beta PDGF receptors. Furthermore, a 40 amino acid domain of PDGF B was identified as responsible for receptor binding properties and the potent transforming phenotype. Two subdomains (106-114 and 135-144) within these 40 PDGF B amino acids were identified as critical for beta receptor interaction. Additional studies of this region identified a 13-amino acid subdomain sensitive to deletions. all of which abrogated PDGF receptor functional activation. Further studies will be directed at identification of competitive antagonists to be used for blocking PDGF-mediated responses. PDGF B's potent transforming phenotype was also dissociated from its membrane-associative property. The differences in PDGF A and B secretory properties was due to differences in the proteolytic processing of analogous functional domains. We further demonstrated that a 15-amino acid domain within PDGF B's final thirty amino acids was responsible for cell surface retention.